Eslicarbazepine acetate is an anticonvulsant active pharmaceutical ingredient approved in Europe and in US for the treatment of epilepsy. Eslicarbazepine acetate is a pro-drug, indeed it deacetylates in vivo releasing the active substance Eslicarbazepine.
Eslicarbazepine is the main metabolite of Oxcarbazepine of formula (III):
since, in vivo, Oxcarbazepine is reduced enantioselectively to Eslicarbazepine, by means of enzymes.
The chemical name of Eslicarbazepine acetate is (S)-10-Acetoxy-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide or 5H-Dibenz[b,f]azepine-5-carboxamide, 10-(acetyloxy)-10,11-dihydro-, (10S)- or (S)-(+)-Licarbazepine acetate and has formula (I):

Eslicarbazepine is the (S) enantiomer of Licarbazepine, it gives optical rotation (+) and has the following formula (II):

Finally, Licarbazepine is the racemic substance constituted of the two enantiomers (S)-(+)-Licarbazepine (Eslicarbazepine) and (R)-(−)-Licarbazepine, said Licarbazepine has therefore the following chemical formula:

In the publication WO9702250, Eslicarbazepine acetate is described for the first time. There are various known synthetic routes to Eslicarbazepine and Eslicarbazepine acetate based upon the following synthetic methods:
1. Resolution of Licarbazepine, including the classic optical resolution (chemical) or the enzymatic resolution, according to the following general scheme:

2. Chemical enantioselective reduction of Oxcarbazepine, according to the following general scheme:

3. Enzymatic enantioselective reduction of Oxcarbazepine, according to the following general scheme:

4. Chemical enantioselective reduction of Acetyloxcarbazepine, according to the following general scheme:

In particular, the first synthetic route of Eslicarbazepine acetate can be generalized with the following scheme of synthesis starting from Oxcarbazepine (III):

This synthetic route is described for the first time in Journal of Medicinal Chemistry, Volume: 42, n. 14, Pages: 2582-2587, 1999, where Oxcarbazepine of formula (III):

is reduced with sodium borohydride to give the racemic alcohol (Licarbazepine), which is then resolved via menthoxyacetate ester.
In the publication WO2002092572 the resolution of the racemic alcohol (Licarbazepine) is described via the corresponding esters of tartaric acid di-O, O′-substituted. Various esters are also specifically described.
Another procedure similar to that already described, but in which different chiral acids are employed, is reported in WO2011091131.
In WO2006056339 a method of chemical resolution is described, of the precursor of Licarbazepine in this case the nitrile intermediate.
The above synthetic routes for optical resolution are long (4 steps starting from Oxcarbazepine) and inefficient (more than half of the Oxcarbazepine is lost), even if subsequent publications (WO2004099153 and WO2006005951 and WO2013008194) describe also methods for the racemization or inversion of configuration of the other enantiomer (R).
The publication IN2009CH00220 describes an enzymatic process for the preparation of Eslicarbazepine acetate by means of the following steps: (a) dissolving the racemic Licarbazepine in a solvent; (b) adding an acylating agent and an enzyme; (c) only the (S)-Licarbazepine is acylated. Said method is based on the enzymatic resolution of acetyl Licarbazepine.
The document WO2011045648 describes an enzymatic resolution of racemic Licarbazepine methoxyacetylated. In one example the racemic Licarbazepine is methoxyacetylated, treated with liquid protease Protex 6 L, extracted, treated with succinic anhydride and then the ester is isolated and worked up to Eslicarbazepine acetate. This synthetic route appears long, laborious and not very efficient.
Another approach for the enzymatic resolution of Licarbazepine is that described in Tetrahedron, 68, (2012), 7613-7618.
In the literature, there are other documents relating to the resolution of racemic Licarbazepine.
In particular, in documents WO2011117885, WO2011138795, IN2011DE00639, WO2012121701, WO2012156987, WO2013008194, additional methods are described for the preparation of Eslicarbazepine by separation of different diasteromeric esters of Licarbazepine. Such esters are prepared by reaction of Licarbazepine with chiral acids and derivatives thereof.
The third approach for the synthesis of Eslicarbazepine is based on the enzymatic enantioselective reduction of Oxcarbazepine. This synthetic approach is efficient and consists of only two synthetic steps from Oxcarbazepine, as in the following scheme:

The publication IPCOM000193904D, dated 2010 March the 14th, discloses some results concerning the reduction of Oxcarbazepine to Eslicarbazepine with enzymes BioCatalytic (Codexis) KRED-114, 119, 130, 101 and enzymes BioCatalytic (Codexis) KRED-NADH-109, 108 and enzyme Enzysource ES-KRED-144. The conversions are low.
The fourth synthetic approach for the synthesis of Eslicarbazepine is through enantioselective reduction of acetyl Oxcarbazepine. This synthetic pathway can be summarized with the following scheme:

This synthetic approach is described for the first time in WO2007117166, wherein Eslicarbazepine acetate is directly prepared by asymmetric hydrogenation of 5H-Dibenz[b,f]azepine-5-carboxamide,10-(acetyloxy)-(compound obtained by acetylation of Oxcarbazepine) in the presence of a chiral catalyst and of a hydrogen source. For example the catalyst can be Rh(COD)(RcSp-DuanPhos)BF4.
But, turning to the second synthetic approach for the preparation of Eslicarbazepine, namely the chemical enantioselective reduction of Oxcarbazepine, there is to be observed that this approach is much more interesting than the one described above for the resolution of the Licarbazepine as it is inherently more efficient (50% of the product is not wasted) and it involves few synthetic steps.
Said process can be generalized with the following scheme:
An interesting publication concerning this second technology is the paper by Noyori, “Ruthenium (II)-Catalyzed Asymmetric Transfer Hydrogenation of Ketones Using a Formic Acid-Triethylamine Mixture”, Journal of the American Chemical Society (1996), 118 (10), 2521-2, teaching of the which have been successfully applied to Eslicarbazepine synthesis, as described in WO2004031155.
The publication WO2004031155 describes an enantioselective “transfer hydrogenation” of Oxcarbazepine, by means of a catalytic system composed of a Ruthenium type metal and one of eight described ligands.
In particular, the examples 1, 2 and 3 of WO2004087168 describe the synthesis of Eslicarbazepine and its enantiomer by enantioselective reduction of Oxcarbazepine according to the following synthetic scheme:

The chiral Ruthenium catalyst used to perform said enantioselective reduction which is, in particular, an asymmetric transfer hydrogenation, is the classical Noyori-type sulfonylated diamine ligands, a catalyst wherein the Rutenium atom is bounded coordinatively (only) to p-cymene ligand.
Unfortunately, said experiments do not disclose the amount of the product produced especially because the product is obtained after purification through flash chromatography and it is just reported that the product shows an e.e. >99%, the description does not discloses the yield neither.
Nevertheless this method shows some important drawbacks such as the need of purify the product through flash chromatography (both experiments 1 and 2) and a huge amount of chiral Ruthenuium catalyst is used, in particular, the molar ratio of the chiral Ruthenium catalyst to Oxcarbazepine of formula (III) is comprised in the range from 1:64 (example 2) to 1:100 (example 2 alternative). Said amount of catalyst, although by one side provides a very high effect in terms of e.e., to the other side it is not suitable for industrial productions, considering the high costs involved of the catalyst.
The PCT application WO2007012793, describes a process for the preparation of Eslicarbazepine via asymmetric reduction of Oxcarbazepine in the presence of a chiral catalyst and a hydrogen source, for example triethylammonium formate. The catalyst is a combination of [RuX2 (L)] 2, where L is a ligand (S, S) or (R, R) of formula:

Also in this case, in the catalyst for performing the enantioselective reduction of Oxacarbazepine to provide Eslicarbazepine the Rutenium atom is bounded coordinatively (only) to p-cymene ligand and the chiral ligand shows (S,S) configuration.
The example 1 of the PCT application WO2007012793, shows that said enantioselective reduction of Oxacarbazepine provides Eslicarbazepine with 95% of isolated molar yield, HPLC purity of 99.6% and 97.8% e.e., wherein the molar ratio of the ruthenium catalyst to Oxcarbazepine used is 1:4000.
In Example 2, Eslicarbazepine is produced with isolated molar yield of 94%, HPLC purity of 99.5%, 97.8% e.e., wherein the molar ratio of the ruthenium catalyst to Oxcarbazepine used is 1:2700.
In Example 4, Eslicarbazepine is produced with isolated molar yield of 88%, HPLC purity of 99.8%, 98.4% e.e., wherein the molar ratio of the ruthenium catalyst to Oxcarbazepine used is 1:5400.
The interesting results in terms of e.e. achieved by the process described in WO2007012793 are achieved controlling the pH of the reaction (see p. 4, I. 12-16), in particular carrying out the enantioselective reduction at pH comprised between 6.5 and 8.0 (see claim 1 and pag. 9 and 10).
In relation to the same technology, that is the enantioselective chemical reduction of Oxacarbazepine to give Eslicarbazepine, also the publication WO2011131315 and the related patent application EP2383261A1 are to be mentioned. In these publications a process of asymmetric reduction of Oxcarbazepine to produce Eslicarbazepine with ee greater than 85% is described, in which a catalyst enantiomerically enriched containing Ruthenium (in many examples a catalyst is described of the type RuX (L1) (L2)) or Rhodium) is used in the presence of a hydrogen donor (for example formic acid) and in the presence of an anionic ion exchange resin (for example IRA-67). It has been indeed found that the presence of said resin provides high conversions with good e.e. (see par. [0005] and claim 1 of EP2383261A1)
As in the previously described prior art documents, asymmetric reduction of Oxcarbazepine to produce Eslicarbazepine is carried in presence of a chiral catalytic catalyst wherein the Rutenium atom is bounded coordinatively (only) to p-cymene ligand and the chiral ligand of formula (I) shows (S,S) configuration.
In example 1 of EP2383261A1, said enetioselective reduction of Oxacarbazepine, in presence of IRA-67 and RuCl[(S,S)-Ts-DPEN](p-cymene), provides Eslicarbazepine with 74% of isolated molar yield, HPLC purity of 99.4% and 99.8% e.e., wherein the molar ratio of the chiral Ruthenium catalyst to Oxcarbazepine used is 1:1340.
In Example 2, Eslicarbazepine is produced in presence of IRA-67 and RuCl[(S,S)-Ts-DPEN](p-cymene) with isolated molar yield of 81%, HPLC purity of 98.8%, 98.1% e.e., wherein the molar ratio of the chiral Ruthenium catalyst to Oxcarbazepine used is 1:1160.
Differently from all the previous chiral Ruthenium catalysts described in WO2004031155 and WO2007012793, the document EP2383261A1 also describes a catalyst having the following general formula:

wherein the Rutenium atom is bounded to a ligand wherein the aryl ring (e.g. p-cymene) is covalently bounded to the chiral diamine ligand through a (CH2)n bridge, and then the aryl group is bounded also coordinatively to the Ruthenium atom, as in the previous catalysts.
In particular, there is only one example where said new catalyst is specifically disclosed (named RuCl[(S,S)-teth-TsDPEN]) and used to carry out the enantiselective reduction of Oxcarbazepine to provide Eslicarbazepine being the second part of example 5 of EP2383261 (par. [0028]) were Eslicarbazepine was obtained, also in presence of IRA-67, with conversion of 83% (after 30 hours) and 86% e.e.
Moreover, the applicant states in par. [0029] that the enantiomeric purity of the product is lower when RuCl[(S,S)-teth-TsDPEN] is used instead of the Noyori-type catalyst RuCl[(S,S)-Ms-DPEN](p-cymene) or RuCl[(S,S)-Ts-DPEN](p-cymene).
From the previous prior art documents it is thus clear as a method for the preparation of Eslicarbazepine having an e.e. lower than 99.0%, typically around 98.0%, is the asymmetric reduction of Oxcarbezepine in presence of chiral Ruthenium catalysts having an aryl group bounded coordinatively, only, to the Ruthenium atom, and mandatorily operating at controlled pH, for example between 6.5 and 8.0, or carrying out the reduction in presence of an anionic ion exchange resin (for example IRA-67).